Project Summary/Abstract Cancer has long been described as a disease of the human genome, and the past two decades of research have largely focused on characterizing the molecular mechanisms that contribute to its origin, progression, and treatment resistance.1,2,28?30 Over the past year, a series of seminal studies have identified significant non-human, microbial contributions in the development and advancement of solid tumors, hematologic malignancies, and germline cancer syndromes, as well as the variable efficacy of chemo- and immunotherapy, shedding light on what may be considered cancer?s ?second? genome (the metagenome).3?11,25 The extent of these microbial contributions across diverse cancer types in the human body and their implications on broader clinical management, however, remain largely unknown.12 Answering basic questions regarding the presence and specificity of such microbes in certain cancer types and cancer stages could guide the rational design of new, microbially-based diagnostics, prognostics, and therapies. Further, addressing more complex questions regarding the interactions of these microbes with cancer and host immune cells in the tumor microenvironment could provide critical insight into the design of personalized immunotherapy, cancer vaccines, and cancer risk profiles, hopefully leading to improved patient outcomes. This proposal builds on a recent analysis of the cancer microbiome in 14,038 primary tumors, through which I have shown that virtually every major tumor type in the human body carries a unique, discriminative microbial signature. Inspired by recent evidence that highlights the role of pathogen-centric immunobiology in cancer development16,17 and the ability of microbes to powerfully modulate the systemic and local immune systems,5,6,8,18 I now hypothesize that the broad existence of these cancer microbes provides an evolutionary advantage for tumors to escape the host immune system?s recognition and response. I also hypothesize that the same immunological processes that are known to shape cancer?s mutational and phenotypic landscapes are concurrently shaping the tumor microbiota. Armed with patient germline HLA allele data and inferred immune cell abundances in the same primary tumors as those in our cancer microbiome study, I believe these hypotheses are finally testable. Aim 1 of this project seeks to investigate them alongside immunotherapy response data.21,22 Complementarily, Aim 2 seeks to define the intratumoral spatial distribution of the cancer microbiome and associated immune cells using a combination of computational and wet lab analyses. These results will contribute to our foundational knowledge on what is becoming the immuno-oncology-microbiome (IOM) axis. The proposed interdisciplinary research will take place at UC San Diego in collaboration with microbiome, systems biology, tumor immunology, pathology, and oncology experts, who serve as mentors and advisors to me. Through their invaluable mentorship, hands-on learning, networking, and additional graduate coursework, I will grow into the translational and effective physician-scientist I so desire to be.